For the past 14 years, our research has been based on a central hypothesis that activation of CSF-1R in neoplastic epithelial cells induces coherent changes in the activation state of signal transduction pathway components, in gene expression, and in the expression of a set of specific cell phenotypes which render non-neoplastic epithelial cells "locally invasive" and "metastatically competent." These changes are the neoplastic epithelial cell counterparts of changes in activation of signal transduction pathways, levels of gene expression and cellular phenotype induced by activated CSF-1R in non-neoplastic macrophages and trophoblast during macrophage activation and placental implantation, physiologically normal, invasive processes dependent on the activation of CSF-IR. Thus, rather than implying that the acquisition of the individual traits which together comprise the phenotypes of "local invasiveness" and "metastatic competence" is random and stochastic, our model proposes that breast, ovarian, and other neoplastic epithelial cells acquire these phenotypes by coopting a normal developmental program expressed by macrophages during activation and by trophoblast cells during placental implantation and regulated by activation of CSF-1Rs. Based on this hypothesis and the experimental results we have obtained which support them, we propose to test whether at least some of the changes in levels of gene expression and signal transduction pathway component activation observed in non-neoplastic epithelial cells after activation of CSF-1R will also be observed when these cells are transfected with another cell surface RTK (i.e. receptor tyrosine kinase) which also renders them Iocally invasive and metastatically competent but not when transfected with other RTKs which do not. We also will test whether pharmacologic agents or genetic manipulations which interfere with these changes in levels of gene expression and signal transduction pathway component activation block local invasion and metastatic dissemination of HC11-fms cells. Finally, we will test whether assay of these CSF-1R-induced changes in human breast and ovarian tumor specimens (where expression of CSF-1R, particularly its activated tyrosine phosphorylated form predicts an adverse prognosis) should likewise correlate with clinical outcome.